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Abstract Background Preoperative chemotherapy is becoming standard therapy for liver metastasis from colorectal cancer, so early assessment of treatment response is crucial to make a reasonable therapeutic regimen and avoid overtreatment, especially for patients with severe side effects. The role of three non-mono-exponential diffusion models, such as the kurtosis model, the stretched exponential model and the statistical model, were explored in this study to early assess the response to chemotherapy in patients with liver metastasis from colorectal cancer. Methods Thirty-three patients diagnosed as colorectal liver metastasis were evaluated in this study. Diffusion-weighted images with b values (0, 200, 500, 1000, 1500, 2000 s/mm2) were acquired at 3.0 T. The parameters (ADC k , K, DDC,α, D s and σ) were derived from three non-mono-exponential models (the kurtosis, stretched exponential and statistical models) as well as their corresponding percentage changes before and after chemotherapy. The difference in above parameters between the response and non-response groups were analyzed with independent-samples T-test (normality) and Mann–Whitney U-test (non-normality). Meanwhile, receiver operating characteristic curve (ROC) analyses were performed to assess the response to chemotherapy. Results Significantly lower values of K (the kurtosis coefficient derived from the kurtosis model) and σ (the width of diffusion coefficient distribution in the statistical model) (P